Zyprexa Controversy Continues

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A risky drug may get wider market

The FDA may approve Zyprexa for kids, despite its significant side

effects in adult use.

By ROBERT FARLEY farley@...

St. sburg Times

December 16, 2007

ph Saunders, who has sued Lilly on behalf of eight patients, says it

defies common sense that Zyprexa became a bestseller.

Gottstein heads PsychRights, a group that fights unwarranted

forced drugging and electroshock to mental patients.

Dr. Egilman, facing possible criminal charges, admitted in writing

that he violated a court order to keep Lilly documents secret.

Shahram Ahari says Zyprexa salesmen were coached how to deal with

doctors worried about weight and diabetes issues.

Dr. Healy, a pharmacology expert, says that with its side effects,

" What you've got is a drug that has very little to recommend it. "

It sounds like a cosmic, FDA joke:

The Food and Drug Administration approves the antipsychotic drug Zyprexa

to treat adults with schizophrenia or bipolar disorder. It becomes a

market wonder, a bestseller. But the side effects turn out to be

dangerous; some patients develop diabetes.

Some 30,000 people sue the manufacturer, Eli Lilly. The pharmaceutical

giant shells out more than $1-billion to settle the cases.

Here comes the punch line:

Though studies show that kids are even more susceptible to Zyprexa's

dangerous side effects, now Lilly wants the government's seal of

approval for adolescents to use it. And the FDA is about to say yes.

* * *

Like a mounted animal head hung as a trophy from the hunt, a framed copy

of a $2.8-million check from Bayer pharmaceutical hangs in the law

office of ph Saunders. The check says: It's my business to sue drug

companies, and I'm good at it.

Saunders practices in Pinellas Park, but hundreds of lawyers like him

across the country have found a niche suing Lilly.

He has eight Zyprexa clients. Most are psychotic. Most suffer from

diabetes, which can cause kidney failure, heart disease, liver damage,

blindness.

They were prescribed Zyprexa during the time doctors swooned over the

big new thing. Approved by the FDA in 1996, Zyprexa was one of a new

class of drugs called atypicals, marketed as powerfully effective for

people suffering the dreadful psychotic breaks of schizophrenia and

bipolar disorder.

And -- this was key -- the new drugs were less likely to cause the

tremors and facial tics that sometimes accompanied older drugs

Zyprexa was deemed so safe, doctors began prescribing it " off-label " to

treat depression, anxiety, ADHD, even sleeplessness. As it turned out,

studies would show that Zyprexa may be the most effective of the new

class of antipsychotic drugs, but it's also most likely to cause serious

weight gain and elevated blood sugar levels.

Saunders says you can't win a lawsuit against a drug company just

because you suffer a side effect. But pharmaceuticals do have a legal

responsibility to warn doctors about known risks.

The tens of thousands of lawsuits contend that Lilly did not fully

disclose risks it discovered during studies conducted to get FDA

approval for Zyprexa, risks that became more apparent in the years after

the drug hit the market.

The preapproval studies lasted six weeks, not nearly time for diabetes

to manifest itself, Saunders says, but there were red flags. Some 29

percent of participants gained significant amounts of weight. Rapid

weight gain puts people at higher risk of developing diabetes.

Lilly spokeswoman Marni Lemons allows that a majority of people who take

Zyprexa gain a lot of weight. And some of them develop diabetes.

But only a small percentage of those who gain weight on Zyprexa develop

diabetes. Also, people with schizophrenia and bipolar disorder are at

higher risk of diabetes no matter what drug they take.

" It's a very complicated subject, " Lemons said. Bottom line: No data

directly finds that Zyprexa causes diabetes.

So why did Lilly pay $1.2-billion to settle 30,000 claims?

" Even when a company has a really strong defense, as we believe Lilly

did, going to court poses very real financial and business risks, "

Lemons said. " Lilly has a responsibility to its shareholders and

employees -- as well as to health care professionals and patients -- to

move beyond this litigation at the lowest possible cost. "

Saunders counters that Lilly treats lawsuits as a cost of doing

business: $1-billion in settlements sounds like a lot, he says, but it's

chump change compared to the tens of billions the company has made since

Zyprexa came on the market.

Lilly has more than private attorneys to worry about. Nine states have

sued, claiming the company illegally promoted unapproved uses of Zyprexa

and downplayed its side effects. The states want to be reimbursed

hundreds of millions for Medicaid dollars they paid for Zyprexa.

In 2003, the FDA directed that not only Zyprexa, but all atypical

antipsychotics carry a warning about increased risk of hyperglycemia and

diabetes.

Lilly continued to market its drug as more effective but no more

dangerous than its competitors. Only this fall did the company agree to

change Zyprexa's label to state that its tendency to increase blood

sugar levels, another diabetes risk factor, is higher than its

competitors.

Asked Saunders: " Why did it take 10 years to warn people about something

they knew from their clinical trials? The reason is clear: They were

making billions and billions of dollars selling it. "

* * *

The telephone call that Gottstein took late last year was a bolt

from the blue.

An attorney in Alaska, Gottstein heads a group called PsychRights, which

presses litigation against forced psychiatric drugging and electric

shock. The caller, a stranger Gottstein never had spoken with, said he

had documents that could help lead Gottstein's group to the promised

land.

The caller, Egilman, worked as a consultant for a law firm that

had thousands of clients suing Lilly over Zyprexa. In that job, he was

given access to thousands of pages of internal Lilly documents, but they

were under protective order; it was illegal for him to make them public.

What happened next is disputed, but a quite furious U.S. district judge,

Jack B. Weinstein, determined this is how his court order was violated:

At the suggestion of a New York Times reporter, Egilman called Gottstein

and -- wink, wink -- suggested he find a separate case in which he could

subpoena the Lilly documents from him. Gottstein could get copies to the

aforementioned reporter before Lilly and the courts could act to stop

it.

The deed done, Lilly officials were furious. As Gottstein put it, " They

came after me like a Panzer division. "

Judge Weinstein, who called it a conspiracy to assist the stealing of

protected documents, tried to get the copies back. But they had hit the

Internet.

There were internal memos, showing Lilly's marketing strategy aimed at

downplaying weight gain and any link to diabetes.

There was a memo from a Lilly employee in 2000 fretting that doctors the

company hired to study the diabetes connection had warned that " unless

we come clean on this, it could get much more serious than we might

anticipate. "

There were letters from doctors who raved about the drug's effectiveness

but warned Lilly that patients were developing diabetes at an alarming

rate. Like this one from 2001, from Dr. Clif Tennison, in Knoxville: " It

is troublesome, frustrating and occasionally irritating to repeatedly

hear the official line that a relationship between Zyprexa and diabetes

is unclear, that diabetes is known to occur more frequently in mentally

ill people with or without meds, etc. We know that.

" But we also know that our Zyprexa patients gain weight and that they do

develop diabetes. It feels as if our concerns are being dismissed, and

that if we would just listen to the experts, we wouldn't worry about

this anymore. "

Egilman and Gottstein paid a price for making the documents public.

Threatened with criminal prosecution, Egilman signed a mea culpathat

said he had provided an " incomplete subset " of the Lilly documents. He

paid the company $100,000, which Lilly donated to charity.

Gottstein, who maintains he did nothing improper, says Lilly is still

going after him, for civil sanctions that could ruin him financially and

for criminal contempt. He says it has threatened to go after his law

license.

When he answered the phone that day, who knew what lay ahead? " I do

think it was important to get this information out. People should be

informed of the risks before they decide to take these drugs. So for me,

it was worth it. "

* * *

Spring 1998. Like zillions of undergrads, Shahram Ahari was finishing

college, looking for that first job. He had finished Rutgers University

with a degree in molecular biology, biochemistry and Asian studies.

A friend's brother landed him an interview with Eli Lilly. The job,

salesman.

Ahari knew zip about pharmaceutical sales, but he loved what he heard:

$50,000 base salary, $10,000 to $15,000 annual bonuses, stock options, a

free car, great health benefits. Meals on a hefty expense account.

To hawk Zyprexa, he says, the pitch was simple: " Encourage doctors to be

the first on their block with a brand-new toy. "

When he made sales calls, he was armed with data from an independent

company that tracked every prescription the doctor made that month. It

helps to know that the doc you are about to pitch prescribes more of

your competitor's drug, say, Risperdal. You can take some gratuitous pot

shots at Risperdal in your pitch.

The job mostly was about befriending doctors and leveraging their

emotions, Ahari says, though favoring them with goodies didn't hurt.

Salesmen wooed doctors with free samples, treated them to expensive

dinners and paid them to give speeches at seminars.

" It practically sold itself, " said Ahari, who sold Zyprexa in New York

from 1998 to 2000.

The gravy train hit some bumps. Reps started hearing from doctors

concerned about patients " blimping up. " Competitors hammered them on it,

derisively twisting Zyprexa's generic name, olanzapine, into

" olanza-pig. "

The Zyprexa sales reps eagerly awaited word from Lilly's brand team on

how they should deal with the weight/diabetes issue. Ahari says this is

what they came up with: Tell doctors to instruct patients to drink a

glass of water before and after they eat, to suppress appetite.

" We'd have to do it with a straight face, " Ahari said, " and after a

while, it just became uncomfortable. "

With doctors he knew well, he said his pitch was blunt: " Would you

rather have a skinny, unwell patient or a fat, stable one? "

Doctors started reporting patients developing diabetes. " That was a big,

scary thing, " Ahari said. If the FDA required that Zyprexa carry a black

box warning about diabetes, " it would have been death, market-wise. "

He says sales reps were instructed to deflect the issues of weight gain

and diabetes. " We were taught to downplay it and negate it, or to change

the topic. "

Lemons, the Lilly spokeswoman, says the company can't be certain what

every sales manager told their sales reps, but " that has never been our

corporate policy. " She questioned Ahari's objectivity because she said

he is now a paid witness for trial attorneys taking on pharmaceutical

companies.

Ahari says he was a paid witness in just one case, which was about

preserving the confidentiality of physicians' prescribing patterns.

Today he does public health research on biological disaster preparedness

at the University of California, San Francisco. He lectures on how sales

reps influence physicians, and he has applied to medical school.

Like many critics, Ahari came to feel Zyprexa was effective, appropriate

for many people. But he believed that the brass at Lilly downplayed the

weight and diabetes problems because the clock on the patents was

ticking. The thinking was, " we may as well milk it while we can. "

* * *

Even with all the lawsuits, Zyprexa remains Lilly's best-seller. Some

22-million people have taken it. In just the first six months this year,

sales topped $2.3-billion.

Lilly can ride the Zyprexa money machine until its patent runs out in

2011. But thanks to a carrot offered by the FDA, the company is in line

to get an extra six months of exclusivity.

That will allow Lilly to keep making top dollar before generic versions

can come on the market and the price falls.

That's where expanding the government's seal of approval to use Zyprexa

on adolescents comes in.

Though the FDA approved Zyprexa only for use on adults with

schizophrenia or bipolar disorder, psychiatrists prescribe it " off

label " to children.

Drug companies had no incentive to study whether giving powerful

antipsychotics to kids is safe, not with doctors already prescribing

their drugs to children by the fistful.

That's why the FDA offered to extend exclusivity of the atypical

antipsychotics by six months if the companies studied their effect in

children.

It has made for a bizarre left-hand/right-hand situation.

On one hand, federal and state investigators are looking into whether

Lilly and other drug companies downplayed risks and illegally promoted

their drugs for unapproved uses.

On the other hand, the FDA is looking into expanding the approved use of

the identical drugs. Already this year, the FDA has approved the

atypicals Risperdal and Abilify for use in adolescents.

Evidence suggests that the dangerous side effects of Zyprexa in adults

are more pronounced in children.

A study published in August compared several atypical antipsychotics in

the treatment of early onset schizophrenia. Kids on Zyprexa gained so

much weight, the Zyprexa arm of the study was discontinued.

Another study, published in the American Journal of Psychiatry in

October, found Zyprexa effective in treating bipolar mania in

adolescents. But in the three-week study, kids on average gained more

than 8 pounds and had elevated glucose and cholesterol levels.

In an accompanying editorial, Dr. Jon M. McClellan, an associate

professor of psychiatry at the University of Washington, wrote that " the

long-term consequences of obesity, dyslipidemia and insulin resistance

-- and the risk of diabetes and cardiovascular disease -- raise serious

questions over the risk-benefit ratio of olanzapine as a first-line

treatment in juveniles. "

McClellan said in an interview that parents tell him their kids on

Zyprexa are always hungry, ravenous even. " A kid comes in and a week

later they've gained 4 pounds, they look puffy, " he said.

Adults taking Zyprexa may gain 5 to 15 pounds in a year, he says, but

kids may gain that in three weeks. Over time, some have gained more than

50 pounds.

A three-person FDA panel that reviewed Lilly's application for approval

of Zyprexa for adolescents had reservations about the studies and

initially recommended denial. The vote was unanimous.

But P. Laughren, director of the FDA's Division of Psychiatric

Products, said the FDA should not follow the expert panel's

recommendation.

Lilly had submitted two studies, with patients roughly split between

sites in the United States and Russia. The three-member FDA team was

troubled that the positive results mostly came from the Russian sites.

But Laughren noted that FDA inspectors visited the Russian sites and

" they found no evidence for fraud. "

He said the side effects in children -- weight gain, somnolence,

sedation, fatigue, dizziness and dry mouth -- were similar to what has

been seen in adults, " however, with some differences in magnitude. "

Those differences need to be reflected on the labeling, Laughren said in

a memo, but he concluded that Zyprexa is " effective and acceptably safe "

for treatment of adolescents with schizophrenia and bipolar disorder.

One of the world's most prominent pharmacology experts shudders at the

prospect of the FDA approving Zyprexa for adolescents.

Dr. Healy, a professor of psychiatry at the University of North

Wales, says that even in adults, Zyprexa should be used only as a

backstop, after other antipsychotics have been tried and failed.

" It ought not to be used in children at all, " he said. " It is going to

be marketed as a safe and gentle drug. It is not a safe and gentle drug.

I think it's an extremely dangerous drug. The idea that it's going to be

given to children on a large scale is quite scary. "

Farley can be reached at farley@... or (727) 893-8603.

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